membrane action potentials & channelopathies dr nithin p g
TRANSCRIPT
Membrane action potentials & Channelopathies
Dr Nithin P G
Membrane Action Potential
Introduction
• Ions
• Channels/Pores/Carriers & Pumps
– Channels- Aqueous channel/ Conformational change/ Action usually regulated/ Open to both environment/ Large number of molecules diffuse across
– Pores- Continuously open to both environment/ No conformational changes/ Always open.
– Carriers & Pumps- Not open simultaneously to both environments/ Binding sites/ Limited number of molecules diffuse across
Carriers & Pumps maintain the concentration gradients
Concepts of Bioelectricity
I= V/R
Concepts of Bioelectricity
+
+-
-
Concepts of Bioelectricity
Concepts of Bioelectricity
What makes ions to move across?
Steady state is reached when the magnitude of the chemical and electric gradients are equal
What makes ions to move across?
• Nernst equationEK =RT/ZF ln [K]2 / [K]1
Where, • T is temperature [370 C]• R is the gas constant • F is the Faraday constant• Z is the valence of ion [1]
• [K]2 and [K]1 are the final concentrations of potassium in compartments 2 and 1, respectively. [150mmol, 5 mmol]
• EK is the equilibrium potential for potassium [-90mV]
– At equilibrium potential net diffusion is 0– All ions try to reach equilibrium i.e., tries to drive the membrane
potential towards its equilibrium potential
What makes ions to move across?
• Goldman–Hodgkin–Katz (GHK) equation
Vm = RT/F ln { PK [K]o+ PNa [Na]o+ PCl [Cl]i / PK [K]i+ PNa [Na]i+ PCl [Cl]o }
Where, PNa, PK, PCl l are the permeabilities of the membrane to sodium, potassium, and
chloride
– At RMP, membrane is permeable mostly to potassium , hence RMP is close to the EK
Simplified circuit of an excitable membrane
Ix = (Vm −Ex )Gx
Some Terms
• Inward current
• Outward current
• Rectifying– Rectifier or diodes allow current only in one direction
• Delayed (s) vs fast/ rapid (r)
• Gating & Inactivation
Gating & Inactivation
• Closing and opening of channels• Voltage, Metabolic, Stretch
Gating & Inactivation
The N-terminal or “ball and chain” mechanism of K channel inactivation
m gate (3)
h gate
Membrane Action Potential
• 2 factors – Electromechanical gradient– Open Channels
• MAP – Sum of AP generated by
different channels [amplitude & direction]
– Number of open channels
Some terms
• Threshold potential- potential at which net inward membrane current becomes large enough to initiate autoregenerative depolarization
• Refractory Period- The interval of time during which the cell cannot be re-excited [Absolute RP]
– Relative RP
– Supranormal Excitability
• Automaticity - spontaneous impulse initiation [results from progressive depolarization of diastolic MP (diastolic depolarization)
Foot Potential
Phase 0• INa [ICaL, Ito, ICaT]
• INa = dV/dtmax [ICaLin SAN,AVN]
• ARP [INa unavailable] RRP [Balance b/w inward & outward current, partial availability of INa, AP with slow upstroke and
conductance] SN [max INa, lower threshold required]
• Post repolarization refractoriness in cases of elevated diastolic potentials [since rate of IO depends
on voltage]
• Na-K ATPase- maintain gradients
• TTX, STX, Class I antiarrhythmics [acts during depolarized states, less atrial action since shorter AP]
Phase1
• Transient outward current
• Beginning of repolarization
• Increased HR & Premature repolarization – only partial availability
• Subepicardium & subendocardium
Ito
Max. Ito availability
Phase 2
• Inward- Ca [ ICaL, INCX] some Na
• Outward- K currents [IKr, IKs, IKur (atrial)] delayed rectifiers
• IKs accumulates during successive cycles at fast ratesincreased IKshorter AP duration [IKs increased by hypercalcemia,
digitalis & catecholamines]
• Na K pump- activates during plateau
• K or Ca- fluctuation in membrane potentials [EAD- persistance of membrane potentials in the ‘window’ of ICaL]
Na & Ca
IK
IKr IKs IKur
Phase 3
• IKs activation
• ICaL full inactivation
• IK1 starts to conduct
• EAD [phase 2 & 3]
IKs
Phase 4IK1 Current- Membrane stabilizing current [inward rectification]
•Others-TWIK-1/2 (KCNK1/6), TASK-1 (KCNK3), and TRAAK (KCNK4)
•Na/K Pump- 3/2 outward; At fast HR RMP more negative
•Low [K]o leads to less IK1 activity, more excitability
•Digoxin inhibits Na/K pump
Phase 0
Phase 1
Phase 2&3
Phase 4
Phase 2&3
Phase 2&3
Phase 2&3
Phase 2&3
Atrial & Ventricular MAP
• Phase 2- increased Calcium current
• Phase 3- increased Kr & Ks activity
• Phase 4- increased IK1
Rate dependency of MAP
• At fast rates, AP duration shortens preservation of diastolic interval– Fast component- incomplete deactivation of delayed rectifiers,
incomplete recovery from inactivation of ICaL, Ito
– Slow component- Na K Pump
• Rate of adaption increased by adrenergic influences
Normal Automaticity•SA node- [-50to-65 mV, diff b/w Emax to Eth is only 30 mV, no INa, depol by ICaL, lower permeability to K [ reduced IK1]
•ICaL [slow responses, recovery from inactivation is slow, RP longer
than AP]
•If- inward Na current, turned on
by hyperpolarization [Autonomic agonists & adenosine]
•ICaT; IKAch&IKAdo[instant
outward shortens AP, Hyperpolarizes E max, reduces diastolic depolarization, reduce HR]
Automaticity-Purkinje Fibers
• Higher IK1 activity [more
complete depol.]
• AP upstroke by INa
• Overdrive suppression [increased rate of Na influx faster Na K pump hyperpolarized Emax further suppression of pacemaker current]
Abnormal automaticity– Directly block K current– Membrane potential to ~ -50
mV IK1 action negligible
Channelopathies
Types
• Brugada Syndrome
• LQTS
• SQTS
• CPVT
Channelopathies
Brugada Syndrome
• Inheritable form of idiopathic ventricular arrhythmia
• LOF Mutations in the SCN5A gene [encodes for the α-subunit of the sodium channel]
• Autosomal Dominant [incomplete or low penetrance]; predominantly in males [presentation at 40yrs]
• Prevalence- 1–5 per 10,000 worldwide [highest in Southeast Asia SUNDS]
• Family history of unexplained sudden death
• Associated ECG abnormalities [transient ST changes Rt precordial leads]
• Increased risk for potentially lethal polymorphic VT or VF [particularly during sleep in the absence of structural heart disease]
ECG Abnormalities
Circulation 2002, 106:2514-2519
Pathophysiology
• Loss of INa
• Unabated Ito current [Ito Epi>>Endo]
• Reduced in conditions increasing ICaL currents (catecholamines), increasing AP duration, block of Ito (quinidine)
Dispersion of repolarization
Pathophysiology
Cardiovascular Research 67 (2005) 367 – 378
Yan and Antzelevitch- Faulty repolarization
Pathophysiology
Cardiovascular Research 67 (2005) 367 – 378
Depolarization Disorder Hypothesis- conduction delay in RVOT
Differential Diagnosis
Diagnosis• Type 1 changes in > 1 right precordial lead (V1 to V3), in the
presence or absence of a Na channel blocker [Ajmaline (1 mg/kg body weight; 10 mg/min), Flecainide (2 mg/kg, max. 150 mg; in 10 minutes), and Procainamide (10 mg/kg; 100 mg/min)] and one of the following
1. Documented VF
2. Self terminating polymorphic VT
3. Family history of SCD (<45 years)
4. Coved type ECGs in family members
5. Electrophysiological inducibility
6. Syncope
7. Nocturnal agonal respiration.
[No other factor to account for the ECG abnormality, only ECG idiopathic Brugada ECG pattern]
• Type 2 Type 1 after drug challenge, drug-induced ST-segment elevation to a value 2 mm
• Type3 Type 1 after drug challenge Circulation 2002, 106:2514-2519
Prognosis
Management
J Am Coll Cardiol 2003;41:1665–71
•Cardiac arrest Survivor (I)•Syncope or Documented VT not resulting in cardiac arrest (IIa) [Annual event rate (2.6% @ 3 yr f/up); device-related complic. (8.9%/year). Inapprop. shocks 2.5 times more frequent]
IIa - electrical storms
IIb - electrical storms
LQTS
• Delayed repolarization of the myocardium, QT prolongation (QTc > 480 msec as the 50th percentile among LQTS cohorts)
• Increased risk for syncope, seizures, and SCD in the setting of a structurally normal heart
• 1/2500 persons.[20% of autopsy-negative sudden unexplained deaths in the young and 10% of SIDS cases]
• Usually asymptomatic, certain triggers leads to potentially life-threatening TdP
• 50% of SCD usually has prior warning/ family history, 5% SCD- sentinel event.
LQTS- channels
LQT11 7q21-q22 AKAP9 Yotiao Potassium (Iks) LQT12 20q11.2 SNTA1 Syntrophin-a1 Sodium (INa)
Pathophysiology
• EAD- R on T VT
• DAD
• Reentry- vortex like (spiral waves) TdP– [HypoK, HypoMg, K blocking
drugs (I, III), bradycardia]
Pathophysiology
Pathophysiology
Diagnosis & Prognosis
Management
• Life style modification
• b blockers in LQTS clinical diagnosis (ecg) [ may be given in pts with molecular diagnosis alone]
• PPI in cases with sustained pause dependent VT +/- QT prolongation
• ICD in survivors of cardiac arrest, may be given in b blocker resistant, considered in high risk groups [LQT2, LQT3, QT>500ms] [Left cardiac sympathetic denervation considered for symptomatic b blocker
resistant]
SQTS
• Structurally intact heart and an increased susceptibility to arrhythmias and sudden death [paroxysmal atrial fibrillation, syncope, and an increased risk for SCD]
• Remarkably accelerated repolarization that is reflected in a shorter-than-normal QTc [<320 msec]
• Syncope 25% pts, Family history of SCD 30% pts, AF in 1/3rd.
• Syncope or cardiac arrest most often during Rest or Sleep.
Pathophysiology
5 genes
Gain of function mutations in K channel-
KCNH2 [IKr] (SQT1), KCNQ1 [IKs] (SQT2), and KCNJ2 [IK1] (SQT3)
Loss of function mutations in ICaL -
CACNA1C (SQT4) and CACNB2b (SQT5)•Atrial & Ventricular-very short APD & RP vulnerable to reentry & easily inducible.•Relatively prolonged T peak-T end interval suggesting augmented transmural dispersion of repolarization
SQTS
• Surface ECG– T symmetric in SQT1 but
asymmetric in SQT [2 to 4]. – SQT2- inverted T waves can
be observed. – SQT5- BrS–like ST elevation
in the right precordial lead
• Quinidine normalizes APD
• ICD may also be indicated
CPVT
• Lethal familial disease that usually manifests in childhood and adolescence [mortality among untreated patients is up to 30% by the age of 40yrs, SCD may be first presentation]
• Stress or exercise-induced bidirectional ventricular tachycardia (biVT) or PMVT leading to syncope and/or SCD [SVT also may be seen]
• Structurally intact heart and no ECG changes at rest.
• Ppted by exercise especially swimming
Pathophysiology
DAD
Ca2+ release through defective SR release (Ryanodine receptor or RyR2)
Management
• Risk stratification is based entirely on clinical considerations.
• Regular follow-up visits, TMT constitute an effective approach for b blocker dose titration and arrhythmia monitoring
• Holter monitoring [sometimes acute emotions ppt]
• Mainstay of Management b Blockers [long term follow up 40% have symptom recurrence]
• ICD in b blocker ineffective cases or survivor of Cardiac arrest
Thank You
MCQ’s
1. False regarding Channels
a) No conformational change occurs
b) Open to both sides
c) Action usually regulated
d) Large number of molecules diffuse through
MCQ’s
2. At equilibrium potentials, net diffusion is
a) Ln [K2/K1]
b) Maximum
c) Zero
d) 10 times more than average
MCQ’s
3. Correct match
a) Phase I- Ina
b) Phase II- ICaL
c) Phase III- If
d) Phase IV- IKur
MCQ’s
4. Membrane stabilizing current
a) IK1
b) INa
c) IKs
d) Ito
MCQ’s
5. False regarding If
a) Inward Ca current
b) Turned on by hyper polarization
c) Increased by adrenergic stimulation
d) Cause for diastolic depolarization
MCQ’s
6. False regarding Brugada Syndrome
a) Inheritable form of idiopathic ventricular arrhythmias
b) LOF mutation in SCN5A
c) Autosomal Recessive
d) Structurally normal heart
MCQ’s
7. Least chance for VT during exercise
a) LQT1
b) LQT2
c) LQT3
d) CPVT
MCQ’s
8. False regarding LQTS
a) QTc > 480msec
b) Structurally Normal Heart
c) Patients with LQTS usually symptomatic throughout their childhood
d) 50% of SCD usually had prior warning
MCQ’s
9. False regarding SQTS
a) Quinidine normalizes APD
b) ICD may be tried
c) Transmural dispersion of repolarization
d) Defective K channels & Na channels
MCQ’s
10. False regarding CPVT
a) Manifest in childhood & early adulthood
b) Structurally normal heart
c) Bidirectional VT or PMVT
d) Ppted usually during deep sleep